(2,3-dihydro-2-benzofuranylmethyl) guanidines and their preparation

ABSTRACT

(2,3-Dihydro-2-benzo-furanylmethyl)guanidines and (2,3-dihydro2-benzofuranylmethyl)-aminoguanidines, having anti-hypertensive activity, are prepared by reacting the corresponding respective 2,3-dihydro-2-benzo-furanylmethylamine or (2,3-dihydro-2benzofuranylmethyl)hydrazine with a guanylating agent, e.g., 2(lower-alkyl)-2-thiopseudourea or cyanamide. Preparation of various intermediates are given, e.g., 2,3-dihydro-2benzofuranylmethyl halides, N-(2,3-dihydro-2benzofuranylmethyl)phthalimides, 2,3-dihydro-2benzofuranylmethylamines and (2,3-dihydro-2benzofuranylmethyl)hydrazines.

United States Patent Bailey [451 Oct. 24, 1972 (2,3-DIHYDRO-2-BENZOFURANYLMETHYL) GUANIDINES AND THEIR PREPARATION [72] Inventor:Denis M. Bailey, East Greenbush,

[73] Assignee: Sterling Drug Inc., New York, NY.

[22] Filed: April 22, 1968 [21] Appl. No.: 723,234

[52] US. Cl ..260/346.2 R, 260/239.1, 260/295,

[51] Int. Cl. ,.C07d 5/42 [5 8] Field of Search ..260/346.2

[56] References Cited FOREIGN PATENTS OR APPLICATIONS 1,202,285 10/1965Germany Primary Examiner-Alex Mazel I Assistant Examiner-Bernard DentzAttomey-Elmer J. Lawson, B. Woodrow Wyatt, Thomas L. Johnson, Robert K.Bair, R. Clifford Bourgeois, William G. Webb and Roger T. Wolfe [5 7-]ABSTRACT Preparation of various intermediates are given, e.g.,

2,3-dihydro-2-benzofuranylmethyl halides, N-(2,3-dihydro-2-benzofuranylmethyl)phthalimides, 2,3-dihydro-2-benzofurany1methylamines anddihydro-2-benzofuranylmethyl)hydrazines.

7 Claims, No Drawings (2,3-DlHYDRO-2-BENZOFURANYLME'I'HYL) GUANIDINESAND THEIR PREPARATION This invention relates to compositions of matterof the class of substituted benzofurans, to their intermediates and totheir preparation.

The invention sought to be patented, in one composition aspect, residesin the compounds of the formula I or II:

NH I i 1 CH2NH NH2 Ha I 5 I 6 1 2 CHQNHNH NHQ where R is hydrogen ormethyl, and, R and R are each hydrogen, The compounds of formula II andtheir above-described preparation and the intennediate compounds offormula V are disclosed and claimed in our copending application Ser.No. 204,309, filed Dec. 2, 1971. halo, lower-alkyl or lower-alkoxy. Theembodiments of this composition aspect of the invention, when testedaccording to standard pharmacological evaluation procedures have theinherent applied use characteristics of having pharmacological activity,e. g., anti-hypertensive activity.

The invention sought to be patented, in its process aspect, resides inthe process of preparing said compounds of formulas I and II whichcomprises reacting, respectively, a compound of the formula HI or IV:

\O CHZNHZ c113 III R1 CHzNHNHi R: IV

with a guanylating agent, e.g., a 2-(lower-alkyl)-2-thiopseudourea orcyanamide.

The invention sought to be patented in another composition aspect,resides in the intermediate compounds of the formula V n g D chloro,bromo, iodo or fluoro, with chloro being preferred because of the readyavailability and cost advantages of chloro intermediates. The termlower-alkoxy, as used herein, e. g.', as one of the meanings for R or Rin formulas II or IV, means alkoxy radicals having from one to sixcarbon atoms, illustrated by methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, amyloxy, n-hexyloxy, and the like. 7 In free'baseform each of the novel compounds of formulas I and II or this inventioninteract with one equivalent of an organic or inorganic acid to form thecorresponding acid addition salt. These acid-addition salts and the freebase of course have a common structural entity. The acid-addition saltsare the full equivalents of the free base form, and the new compound ofthis invention includes. both the free base and the acid-addition saltsthereof. The novel feature of the compound of the invention thus residesin the concept of the base and the cationic forms of the new compoundsof formula I or II and not in any particular acid moiety or acid anionassociated with the salt form of the compounds; rather, the acidmoieties or anions which can be associated in the salt form are inthemselves neither novel nor critical and therefore can be any acidanion or acid-like substance capable of salt formation with bases. Itwill be appreciated that in aqueous solutions the base form and thewater-soluble acid-addition salt form of the compounds of the inventionpossess a common protonated cation or ammonium ion.

Thus the acid-addition salts discussed above and claimed herein areprepared from any organic acid, inorganic acid (including organic acidshaving an inorganic group therein), or organo-metallic acid asexemplified by organic monoand poly-carboxylic acids such as found, forexample, in Beilsteins Organische Chemie, 4th Ed., Volumes III, IV, IX,X XIV, XVII, XIX, XXI, XXII, and XXV; organic monoand polysulfonic and-sulfinic acids such as found, for example in Beilstein volumes VI, XI,XVI, and XXII; organic phosphonic and phosphinic acids such as found,for example, in Beilstein volumes XI and XVI; organic acids of arsenicand antimony such as found, for example in Beilstein volumes XVII, XXII,and XXV; acidic ionexchange resings; and inorganic acids of .any acidforming element or combination of elements such as found in Mellow,Comprehensive Treatise on Inorganic and Theoretical Chemistry, LongmansGreen and Co., New York, NY. volumes I-XVI. In addition, othersaltforrning compounds which are acidic in their chemical properties butwhich are not generally considered as acids in the same sense ascarboxylic or sulfonic acids are also considered to be among thenumerous acids which can be used to prepare acid-addition salts of thecompounds of the invention. Thus there is also comprehended acidicphenolic compounds such as found, for activited or acidic hydrogenatoms, as for example, picrolonic acid, or barbituric acid derivativeshaving an acidic proton such as found, for example, in Cox et al.Medicinal Chemistry, vol. IV, John Wiley and Sons,

-Inc., New York, NY. (1959).

Representative acids for the formation of the acidaddition salts includeformic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid,trifluoroacetic acid, malic acid, fumaric acid, succinic tic acid,glycolic acid, gluconic acid, saccharic acid,

ascorbic acid, penicillin, benzoic acid, phthalic acid, salicylic acid,acetylsalicylic acid, 3,5-dinitrobenzoic acid, anthranilic acid, cholicacid, Z-pyridinecarboxylic acid, 3-hydroxy-2-naphthoic acid, picricacid, quinic acid, tropic acid, 3-indoleacetic acid, barbituric acid,sulfamic acid, methanesulfonic acid, ethanesulfonic acid, isethionicacid, benzenesulfonic acid, ptoluenesulfonic acid, saccharin,butylarsonic acid, methanephosphonic acid, acidic resins, hydrofluoricacid, hydrochloric acid, hydrobrornic acid, hydriodic acid, perchloricacid, nitric acid, sulfuric acid, phosphoric acid, hydrocyanic acid,phosphotungstic acid, molybdic acid, arsenic acid, and the like.

The acid-addition salts areprepared in conventional fashion, forinstance either by direct mixing of the acid and the base or, when thisis not appropriate, by dissolving either or both of the acid and thebase separately in water or an organic solvent and mixing the twosolutions, or by dissolving both the acid and the base together in asolvent. The resulting acid-addition salt is isolated by filtration, ifit is insoluble in the reaction medium, or by evaporation of thereaction medium to leave the acid-addition salt as a residue.

The acid-addition salts of the compounds of formula I or II are useful,in many instances, not only as pharmacological agents but are alsouseful, in all instances, as characterizing or identifying derivativesof the free base and in isolation or purification procedures. Moreover,the acid-addition salts, react with strong bases, such as alkali metalhydroxides, to generate the free base; and accordingly all of the salts,regardless of considerations of solubility, toxicity, physical form, or

the like of a particular species of acid-addition salt, are

useful for the purposes of our invention since they are sources of thefree base.

It will be appreciated from the above that if one or more of thecharacteristics, such as solubility, molecular weight, physicalappearance, toxicity, or the like of agiven acid-addition salt render itless suitable or un-' suitable for the particular desired purpose, asfor example, use as an anti-hypertensive agent or in an isolation orpurification procedure, or the like, the acid-addition salt can beconverted to the free base and then to another, more suitableacid-addition salt, for instance, a pharmaceutically-acceptable saltwhen a pharmaceutical use is involved.

The molecular structures of the compounds of formula I or II of theinvention are assigned on the basis of evidence provided by infrared(IR), ultraviolet (UV) and nuclear magnetic resonance (NMR) spectra, bychromatograph mobilities, and, by the correspondence of calculated andfound values for the elementary analyses for representative examples.

The manner and process of making and using the invention will now begenerally described so as to enable a person skilled in the art ofmedicinal chemistry to make and use the same, as follows:

The reaction of the compound of formula III or IV with a guanylatingagent is carried out preferably by heating the reactants in a mutualsolvent, e.g., water, a lower-alkanol such as methanol, ethanol,isopropyl alcohol or other water-miscible alcohols or solvents, or

mixtures of water and said alcohols or solvents. The

reactants can be used in free base form or in the form of theiracid-addition salts, preferably salts with strong inorganic acids ororganic sulfonic acids. The preferred guanylating agent is a2-(lower-alkyl)-2-thiopseudourea, e.g., 2-methyl-2-thiopseudourea,2-ethyl-2-thiopseudourea. Also useful is cyanamide.

The intermediate benzofuranylmethyDhydrazines of formula IV areconveniently prepared from corresponding 2,3-dihydro-2-benzofuranylmethyl halides, e.g., bromides, iodides, using generallyknown procedures. For example, the2,3-dihydro-2-benzofuranylmethylamines are prepared by first reacting acorresponding 2,3-dihydro-2- benzofuranylmethyl bromide or iodide withan alkali metal phthalirnide, e.g.,potassium phthalimide, and thenreacting the resulting N-(2,3-dihydro-2-benzofuranylmethyl)phthalirnidewith hydrazine hydrate. The (2,3-dihydro-2-benzofuranylmethyl)hydrazinesare prepared by reacting the corresponding 2,3-dihydro-2benzofuranylmethyl bromide or iodide directly with hydrazine hydrate.

The starting 2,3-dihydro-2-benzofuranylmethyl halides are prepared inseveral steps using conventional procedures and known 2-allylphenols.For example, in one procedure, the appropriate 2-ally1phenol is reactedwith mercuric chloride to form a 2,3-dihydro-2- benzofuranylmethylmercuric chloride, the latter is reacted with potassium iodide to formthe corresponding 2,3-dihydro-2-benzofuranylmethyl mercuric iodide,which is then reacted with iodine and potassium iodide to form the2,3-dihydro-2-benzofuranylmethyl iodide. In another procedure, the2-allylphenol is acetylated by reaction with acetic anhydride, theresulting 0-acety1- 2- allylphenol is reacted with bromine to form the0- acetyl-2-(2,3-dibromopropyl)phenol, which is then reacted with analkali alkoxide, e.g., sodium methoxide, in a suitable solvent, e.g.,ethanol, to form the 2,3- dihydro-2-benzofuranylmethyl bromide.

Further illustrative preparations of theabove-noted intermediates andstarting materials are given hereinbelow.

I The foregoing discussion is offered to illustrate the various aspectsof the invention and not to limit its scope. The invention is furtherillustrated by the following examples.

1. 5-Chloro-2,3-dihydro-2-benzofuranylmethyl iodide This compound wasprepared in three steps starting with 2-allyl-4-chlorophenol as follows:A solution containing 131 g. of 2-allyl-4-chlorophenol in 500 ml. ofethanol was added to a solution of 220 g. of mercuric chloride in amixture of 1500 ml. of water and 1000 ml. of ethanol. After the solutionhad been stirred for 1 hour at room temperature (about 2530 C.), 300 ml.of water was added whereupon a heavy oil separated. An additional 100 g.of mercuric chloride was added to the reaction mixture and stirring wascontinued for more minutes, after which time the oil had solidified. Thesolid was collected, washed with water and dried overnight to yield 298g. of 5-chloro-2,3-dihydro-2- benzofuranylmethyl mercuric chloride. Asmall sample was recrystallized from ethanol and found to melt at2,3-dihydro-2-benzofura'nyl- .methylamines of formula III and(2,3-dihydro-2- 90-92 C. A 296 g. portion of 5-chloro-2,3-dihydro-2-benzofuranylmethyl mercuric chloride was powdered and suspended in asolution containing 332 g. of potassium iodide in 1500 ml. of water andthe resulting suspension was stirred and heated to boiling where it wasmaintained for ten minutes. The stirred mixture was allowed to coolandeventually chilled in an ice bath whereupon a heavy gummy precipitateof 5- chloro-2,3-dihydro-2-benzofuranylmethyl mercuric iodide onlypartially solidified after 2 hours. To the mixture was added another1500 ml. of water and the resulting reaction mixture was boiled withstirring for about 2 hours at the end of which time the volume was about1 liter. Another 3 liters of water and 120 g.-of potassium iodide wereadded and the mixture stirred at 80 C. while 186 g. of iodine was added.The mixture,

was stirred for 30 minutes and then stored at C. overnight. The mixturewas extracted with chloroform. The extract was washed with aqueouspotassium iodide solution, dried over anhydrous sodium sulfate andconcentrated in vacuo to remove the solvent. The remaining oil wasdistilled under reduced pressure to yield three fractions, b.p. 1 101 14C. at 0075-0080 mm, all of which were contaminated with iodine. Thefractions were combined, diluted with chloroform, washed with 10 percentaqueous sodium bisulfite solution and evaporated to remove thechloroform to yield 144 g. of 5-chloro-2,3-dihydro-2-benzofuranylmethyliodide as a pale yellow oil. 2.2,3-Dihydro-5,7-dimethyl-2-benzofuranylmethyl iodide To a solutioncontaining 181 g. of mercuric chloride in 3400 ml. of water was addeddropwise with stirring 103.8 g. of 6-allyl-2,4-xylenol and the resultingmixture was stirred overnight (about 15 hours). The crystallineprecipitate was collected, washed with water and airdried to yield2,3-dihydro-5,7-dimethyl-2rbenzofuranylmethyl mercuric chloride, a smallsample of which was recrystallized from absolute ethanol and found tomelt at 95.5-96.4 C. The 2,3-dihydro-5,7-dimethyl-2- benzofuranylmethylmercuric chloride was ground into a fine powder and added to a solutioncontaining 318 g. of potassium iodide in 3200 ml. of water. Theresulting mixture was heated with stirring to reflux, maintained atreflux for 5 minutes and then allowed to cool while standing overnight.To the mixture containing 2,3- dihydro-5,7-dimethyl-2-benzofuranylmethylmercuric iodide as a precipitate was added 30 g. of potassium iodide andthe resulting mixture heated to reflux for one hour while 163 g. ofiodine was added. The mixture was extracted with chloroform. Thechloroform extract was washed with 100 ml. of 20 percent potassiumiodide solution and than four times with 200 ml. of sodium thiosulfatesolution containing 1 g. of sodium thiosulfate per 20 ml. of solution.The chloroform solution was then washed successively with three 250 ml.portions of 10 percent sodium bicarbonate solution and two 250 ml.portions of hot water, then dried by swirling over anhydrous sodiumsulfate and filtered through anhydrous sodium sulfate. The filtrate washeated on a steam bath, treated with decolorizing charcoal, filteredthrough infusorial earth and concentrated in vacuo to remove thesolvent. The remaining oil was distilled under reduced pressure to yield124.6 g. of oil at 121l24 C. and 1.2 mm. The oil was dissolved in ml. ofbenzene and the benzene solution washed with three 100 ml. portions of 5percent aqueous sodium thiosulfate. The aqueous wash was extracted withtwo 100 ml. portions of chloroform. The organic phases were combined,washed with 1 ml. of water, dried over anhydrous sodium sulfate,filtered through anhydrous sodium sulfate and concentrated on the steambath to remove the solvent. The remaining oil was distilled underreduced pressure to yield 1 17.9 g. of2,3-dihydro-5,7-dimethyL2-benzofuranylmethy1 iodide, b.p. ll0-l 24 C. at05-13 mm.

3. 2,3-Dihydro-7-methyl-2-benzofuranylmethyl bromide This compound wasprepared in three steps starting with 6-a1lyl-2-cresol, as follows: Asolution containing 245 g. of 6-allyl-2-cresol in 500 ml. of aceticanhydride was refluxed for 3 hours and then concentrated under reducedpressure. When an attempt at vacuum distillation indicated incompletereaction, the distillation was stopped and the fractions and pot residuewere recombined, treated with ml. of acetic anhydride and 150 ml. ofpyridine, and the resulting solution allowed to stand over the weekendat room temperature (about 25-30 C). The solution was poured into amixture of ice and water and the aqueous mixture was extracted withbenzene. The benzene extract was washed successively with dilute aqueoushydrochloric acid, 10 percent aqueous sodium bicarbonate and water;dried over anhydrous sodium sulfate; and, evaporated. The residue wasdistilled under reduced pressure to yield 220.7 g. of2-acetoxy-3-allyltoluene, b.p. 138-14l C. at 26-265 mm. The2-acetoxy-3-allyltoluene was dissolved in 800 ml. of carbon disulfideand the solution treated with 2 g. of powdered anhydrous sodiumcarbonate. The mixture was cooled below 0 C. and'to it was addeddropwise with stirring over a period of 2% hours a solution of g. ofbromine and 200 ml. of carbon disulfide. The solvents were-removed underreduced pressure and the residual oil mixed with one liter of n-hexaneand cooled. When the product separated as an oil, the mixture wasevaporated to remove the n-hexane and the remaining 2-acetoxy-3-(2,3-dibromopropyl)toluene was diluted to a volume of 1000 ml. withabsolute ethanol. A solution containing 16.2 g. of sodium methoxide in200 ml. of absolute ethanol was added with stirring to a solution cooledbelow 10 C. and containing 100 ml. of ethanol and 250 ml. of the aboveethanol solution of 2-acetoxy-3-(2,3- dibromopropyl)-toluene. Aftercompletion of the addition (1 hour), the mixture was stirred withoutcooling for 105 minutes and then refluxed for 30 minutes. The solventswere removed under reduced pressure and the residue taken up inchloroform and water. The chloroform layer was separated, dried overanhydrous sodium sulfate, evaporated to remove the solvent and theremaining oil distilled at reduced pressure to yield 31.5 g. of2,3dihydro-7-methyl-2-benzofuranylmethyl bromide, b.p. 86-89 C., at 0.7mm.

Other 2,3-dihydro-2-benzofuranylmethyl iodides prepared by following the3-step procedure described in Example A-l starting with a molarequivalent quantity of the appropriate 2-allylphenol in place of2-allyl- 4-chlorophenol are as follows: 5-bromo-2,3-dihydro-2-benzofuranylmethyl iodide from 2-allyl-4-bromophenyl;2,3-dihydro-4,6-dimethyl-2-benzofuranylmethylmethoxy-2-benzofuranylmethyl iodide from 2-allyl-4- methoxyphenol;2,3-dihydro-6-methoxy-2-benzofuranylmethyl iodide from2-allyl-5-methoxyphenol;-tbutyl-2,3-dihydro-7-methyl-2-benzofuranylmethyl iodide from6-allyl-4-t-butyl-2-cresol; 5-n-butyl-2,3- dihydro-2-benzofuranylmethyliodide from 2-allyl-4-nbutylphenol;7-chloro-2,3-dihydro-2-benzofuranylmethyl iodide from2-allyl-6-chloro-phenol; S-ethoxy- 2,3-dihydro-2-benzofuranylmethyliodide from 2-allyl- 4-ethoxyphenol;2,3-dihydro-6-n-propyl-Z-benzofuranylmethyl from2-allyl-5-npropylphenol; 7-ethyoxy-2,3-dihydro-5-methyl-2-benzofuranylmethyl iodide from2-allyl-6-ethoxy-4-cresol; 5-t-butyl-2,3-dihydro-2- benzofuranylmethyliodide from 2-allyl-4-t-butylphenol; 7-( 2-butyl 2 ,3-dihydro-2-benzofuranylmethyl iodide from 2-allyl-6-(2-butyl)phenol;2,3- dihydro-4,6-dimethoxy-2-benzofuranylmethyl iodide from2-allyl-3,S-dimethoxyphenol; 2,3-dihydro-6,7-dimethoxy-2-benzofuranylmethyl iodide from 6-allyl- 2,3-dimethoxyphenol;7-ethoxy-2,3-dihydro-2- benzofuranylmethyl iodide from2-allyl-6-ethoxyphenol; 2,3-dihydro-4-methyl-2-benzofuranylmethyl iodidefrom 2-allyl-3-cresol; 2,3-dihydro-6-methyl-2- benzofuranylmethyl iodidefrom 6-allyl-3-cresol; 6- chloro-2,3-dihydro-2-benzofuranylmethyl iodidefrom 2-allyl-5-chlorophenol; and, 5-'ethyl-2,3-dihydro-2-benzofuranylmethyl iodide from 2-allyl-4-ethylphenol.

mides W l. N-( 2,3-dihydro-7-methyl-2-benzofuranylmethyl)- phthalimide Amixture containing 22.7 g. of 2,3-dihydro-7- methyl-2-benzofuranylmethylbromide and 18.5 g. of potassium phthalimide in 100 ml. ofdirnethylformamide was heated on a steam bath with stirring for 7% hoursand then allowed to stand overnight at room temperature. A small sampleof the reaction mixture was diluted with water and yielded crystalswhich were collected. The reaction mixture was poured into 500 ml. of amixture of ice and water; the resulting gummy precipitate was trituratedwith the crystals obtained from the small sample. After about 30minutes, the product solidified. The solid was collected, washed withwater, crystallized from isopropyl alcohol and then recrystallized fromisopropyl alcohol to yield 17.8 g. ofN-(2,3-dihydro-7-methyl-2-benzofuranylmethyl)phthalimide, l39.8l42.6 C.(com) 2. N-(2,3-dihydro-5,7-dimethyl-2-benzofuranylmethyl)-phthalimide Amixture containing 57.5 g. of 2,3-dihydro-5,7-dimethylbenzofuranylmethyl iodide and 37.1 g. of potassium phthalimidein 350 ml. of dimethylformamide was heated on a steam bath overnight(about 15 hours) with stirring. The solvent was taken off under reducedpressure and the residue taken up in about 300 ml. of chloroform. Thechloroform solution was washed successively with two 250 ml. portions ofwater, two 125 ml. portions of 10 percent aqueous sodium hydroxidesolution and again with one 250 ml. portion of water. The chloroformsolution was dried over anhydrous sodium sulfate, filtered through an-N-(Z,3-dihydro-2-benzofuranyl-methyl)phthalihydrous sodium sulfate andthe filtrate concentrated in vacuo to remove the chloroform. On standingovernight, the syrupy residue yielded a few crystals and on rubbing witha glass rod the entire residue became crystalline. The crystallinematerial was dissolved in 500 ml. of hot isopropyl alcohol, filtered andthe filtrate seeded with one of the aforesaid crystals. The resultingcrystalline precipitate was collected, washed with small portions ofmother liquor and dried in' vacuo at 55 C. overnight to yield 25.1 g. ofN-(2,3-dihydro- 5,7-dimethyl-Z-benzofuranylmethyl)phthalimide, m.p.136.8-138.4C.(corr.)

1. 2,3-Dihydro-7-methyl-2-benzofuranylmethylamine A mixture containing12.8 g. of N-'(2,3-dihydro-7- methyl-2-benzofuranylmethyl)phthalimide, 7ml. of hydrazine hydrate and ml. of ethanol was refluxed with stirring.After about twenty minutes of refluxing, the entire reaction mixture hadsolidified. After 65 ml. of ethanol and another 7 ml. of hydrazinehydrate had been added, the mixture combined with the mother liquor fromthe recrystallization of Example B-1 (200 ml. of isopropyl alcoholcontaining 1.2 g. of N-(2,3-dihydro-7-methyl-2-benzofuranylmethyl)-phthalimide). The resultingmixture was refluxed with stirring for 1 hour. The solid was collectedand washed with isopropyl alcohol. The filtrate was allowed to standovernight and the additional separated solid collected. The filtrate wasevaporated under reduced pressure to yield a mixture of a solid and anoily material. The oily solid was triturated with 25 ml. of isopropylalcohol and the solid collected by filtration. The solid was washed withanother 25 ml. of isopropyl alcohol and the combined filtrate andwashings were evaporated to yield 6.8 g. of2,3-dihydro-7-methyl-2-benzofuranylmethylamine, which was used directlyin the following step (Example E-l2,3-Dihydro-5,7-dimetl1yl-2-benzofuranylmethylamine To a solutioncontaining 38.6 g. of N-(2,3-dihydro-5,7-dimethyl-Z-benzofuranylmethyl)phthalimide in a mixture of isopropylalcohol and a small amount of methanol (total volume about 800 ml.)heated to reflux on a steam bath was added with stirring 31 g. ofhydrazine hydrate and refluxing with stirring was continued for minutes.After the reaction mixture had been allowed to stand at room temperatureovernight, the precipitated solid was filtered off and washed withisopropyl alcohol. The filtrate and washings were combined andconcentrated in vacuo to remove the solvents. The residual oily materialwas distilled under reduced pressure to yield 7.7 g. of 2,3-dihydro-5,7-dimethyl-2-benzofuranylmethylamine, b.p. 77-94 C. at 0.06-0.100 mm.

Q QQ-dihydro-2-benzofuranylmethybhydrazines sure and the residue treatedwith an excess of 10 percent aqueous sodium hydroxide solution. Thebasic mixture was extracted with chloroform. The chloroform extract wasdried over anhydrous sodium sulfate, filtered and the chloroform removedunder reduced pressure. The residue was distilled under vacuum to yield15.4 g. of (2,3-dihydro-7-methyl-2- benzofuranylmethyl)hydrazine, b.p.110-l 13 C. at 0.5 mm. 2.(-Chloro-2,3-dihydro-2-benzofuranylmethyl)hydrazine v To a stirredrefluxing solution containing 80 g. of 95 percent hydrazine hydrate in100 ml. of absolute ethanol was added dropwise over an hour withstirring a solution of 72 g. of5-chloro-2,3-dihydro-2-benzofuranylmethyl iodide in 100 ml. of absoluteethanol. The reaction mixture was heated for twenty-two hours and thenthe solvents and excess hydrazine were removed under reduced pressure.The residue was diluted with 125 ml. of percent aqueous sodium hydroxidesolution, 100 ml. of brine and 100 m1. of water. The aqueous mixture wasextracted with chloroform and then saturated with solid sodium chlorideand extracted further with chloroform. The combined chloroform extractswere dried over anhydrous potassium carbonate and evaporated in vacuo toremove the chloroform. The remaining oily residue was distilled underreduced pressure to yield 22.5 g. of (5-chloro-2,3-dihydro-2-benzofuranylmethyl)-hydrazine, b.p. l18-133.C. at 0.09-0.22 mm.

Other (2,3-dihydro-2-benzofuranylmethyl)hydrazines prepared by followingthe procedure of Example D-2 using a molar equivalent quantity of theappropriate corresponding 2,3- dihydro2-benzofuranylmethyl iodide inplace of 5- chloro-2,3-dihydro-2-benzofuranylmethyl iodide are asfollows: (5-bromo-2,3-dihydro-2-benzofuranylmethyl )hydrazine,2,3-dihydro-4,6-dimethyl-2- benzofuranylmethyl)hydrazine,(2,3-dihydro-5- methyl-2-benzofuranylmethyl)-hydrazine, (5,7-dichloro-2,3-dihydro-2-benzofuranylmethyl)hydrazine,(2,3-dihydro-5-methoxy-2-benzofuranylmethyl)hydrazine, (2,3dihydro-6-methoxy-2- benzofuranylmethyl)hydrazine,(5-t-butyl-2,3-dihydro- 7-methyl-Z-benzofuranylmethyl)hydrazine,(5-nbutyl- 2,3-dihydro-2-benzofuranylmethyl)hydrazine, (7-chloro-2,3-dihydro-2-benzofuranylmethyl)hydrazine,(5-ethoxy-2,3-dihydro-2-benzofuranylmethyl)hydrazine,(2,3-dihydro-6-n-propyl-2-benzofuranylmethyD-hydrazine,(7-ethoxy-2,3-dihydro-5- methyl-2-benzofuranylmethyl) hydrazine,(S-t-butyl- 2,3-dihydro-2-benzofuranylmethyl )hydrazine, [7-( 2-butyl)-2,3-dihydro-Z-benzofuranylmethyl]hydrazine,(2,3-dihydro-4,6-dimethoxy-2-benzofuranylmethyl)hydrazine,(2,3-dihydro-6,7-dimethoxy-2- benzofuranylmethyl)hydrazine,(7-ethoxy-2,3-dihydro- 2-benzofuranylmethyl)hydrazine, (2,3-dihydr0-4-methyl-2-benzofuranylmethyl)hydrazine, (2,3-dihydro-6-methyl-2-benzofuranylmethyl)hydrazine,

( 6-chloro-2, 3-dihydro-2-benzofuranylmethyl hydrazine and(S-ethyl-2,3-dihydro-2-benzofuranylmethyl)hydrazine.

Y -Z-benzofuranylmethyllgn iqt l(2.3-Dihydro-7-methyl-2-benzofuranylmethyl )guanidine iii A mixturecontaining 6.8 g. of 2,3-dihydro-7-methyl- 2-benzofuranylmethylamine and7.7 g. of 2-ethyl-2- thiopseudourea hydrobromide in ml. of isopropylalcohol was refluxed for 6 hours and then allowed to stand at roomtemperature over the weekend. The reaction mixture was evaporated invacuo to yield a gummy residue which partially crystallized on standing.Trituration of the mixture with isopropyl alcohol completedcrystallization. The solid was recrystallized from isopropyl alcohol,washed with cold isopropyl alcohol and dried at 50 C. and 20 mm. for 24hours to yield 5.8 g. of(2,B-dihydro-7-methyL2-benzofuranylmethyl)-guanidine as itshydrobromide, m.p. l82.8-1 89.0 C. (corn) 2.(2,3-Dihydro-5,7-dimethyl-2-benzofuranylmethyl)- guanidine A mixturecontaining 5.95 g. of 2,3-dihydro-5,7-dimethyl-2-benzofuranylmethylamine, 4.75 g. of 2-methyl-2-thiopseudourea sulfate and 25 ml. of water was refluxed withstirring for 4 hours and allowed to cool to room temperature. Theprecipitate was collected, washed with small portions of ice water andcool isopropyl alcohol, recrystallized from water, dried in vacuo at C.overnight to yield 3.3 g. of (2,3- dihydro-5,7-dimethyl-2-benzofuranylmethyl guanidine asits sulfate, m.p.l38.0144.0 C.

F. (2,3-dihydro-2-benzofuranylmethyDaminoguanidine ,M.

r (2,3-Dihydro-7-methyl-2-benzofuranylmethyl)aminoguanidine A mixturecontaining 15.4 g. of (2,3-dihydro-7-methyl-2-benzofuranylmethyl)hydrazine, 12.1 g. of 2-methyl-2-thiopseudourea sulfate and 100 ml. of water was refluxed withstirring for 4 hours. The solvent was removed in vacuo and the gummysolid residue was recrystallized from methanol-acetonitrile. Theresulting gummy solid was washed with acetonitrile and then stirred witha mixture of 100 ml. of isopropyl alcohol and 5 m1. of methanol at 20-25C. for 4 hours. The solid was collected, dried overnight at 50 C. and 20mm. and then recrystallized first from methanolisopropyl alcohol andthen water to yield 2.9 g. of(2,3-dihydro-7-methyl-2-benzofuranylmethyl)aminoguanidine as itssulfate, m.p. 190.01 96.0 C. (com) 2.(5-Chloro-2,3-dihydro-2-benzofuranylmethyl)amino-guanidine A mixturecontaining 11.4 g. of (5-chloro-2,3-dihydro-2-benzofuranylmethyl)hydrazine, 8.0 g. of 2-methyl-Z-thiopseudourea sulfate, ml. of water and 15 ml. of isopropylalcohol was refluxed with stirring for 6 hours and then allowed to coolto room temperature and stand overnight. The gummy precipitate wascollected. An attempt to recrystallize this material frommethanolacetonitrile yielded an oil which crystallized on standing. Thematerial was then dissolved in one liter of methanol and the methanolsolution passes through a column of chloride-form ion exchange resin(800 ml. wet volume), with a total elution time of 6 hours. Another oneliter of methanol was used to wash the column. The combined eluents wereevaporated under reduced pressure and the residue taken up in 5 percentaqueous hydrochloric acid. The addition of 6N aqueous hydrochloric acidcaused the formation of a cloudy solution. The mixture was washedsuccessively withchloroform and ether, and then evaporated under "11reduced pressure to yield a solid. The solid was recrystallized oncefrom isopropyl alcohol-ether and once from. concentrated hydrochloricacid to yield 3.4 g. of(-chloro-2,3-dihydro-2-benzofuranylmethyl)aminoguanidine as itssesqui-hydrochloride, m.p'. l58.0l68.0 C. (corn) Other(2,3-dihydro-2-benzofuranylmethyl)aminoguanidines prepared by followingthe procedure described in Example F-l using a molar equivalent quantityof the corresponding appropriate (2,3-dihydrofuranylmethyl)hydrazine inplace of (2,3- dihydro-7-methyl-2-benzofuranylmethyl)hydrazine are asfollows: (5-bromo-2,3-dihydro-2-benzofuranylmethyl)aminoguanidine,(2,3-dihydro-4,6-dimethyl-2- benzofuranylmethyl)aminoguanidine,(2,3-'dihydro-5- rnethyl-2-benzofuranylmethyl)aminoguanidine, (5,7-dichloro-Z,3 dihydro-2-ben2ofuranylmethyl)aminoguanidine,(2,3-dihydro-5-methoxy-2- benzofuranylmethyl)aminoguanidine,(2,3-dihydro-6- methoxy-2-benzofuranyl-methyl)aminoguanidine,(5-tbutyl-2,3-dihydro-7-methyl-2-benzofuranylmethyl)aminoguanidine,(5-n-butyl-2,3-dihydro-2- benzofuranylmethyl)aminoguanidine,(7-chloro-2,3- dihydro-2-benzofuranylmethyl)-aminoguanidine, (5-ethoxy-2,3-dihydro-2-benzofuranylmethyl )aminoguanidine,(2,3-dihydro-6-n-propyl-2- benzofuranylmethyl)aminoguanidine,(7-ethoxy-2,3- dihydro-S-methyl-2-benzofuranylmethyl)- aminoguanidine,(5-t-butyl-2,3-dihydro-2-benzofuranylmethyl)aminoguanidine,[7-(2-butyl)-2,3- dihydro-2-benzofuranylmethyl]aminoguanidine, (2,3-dihydro-4,6-dimethoxy-2-ben2ofuranylmethyl)aminoguanidine,(2,3-dihydro-6,7-dimethoxy 2-benzofuranylmethyl)aminoguanidine,7-ethoxy-2,3- dihydro-2-benzofuranylmethyl)aminoguanidine, (2,3-dihydro-4-methyl-2-benzofuranylmethyl )aminoguanidine, 2, 3-di-hydro-6-methyl-2- benzofuranylmethyl)aminoguanidine, (6-chloro-2,3-

dihydro-2-benzofuranylmethyl)aminoguanidine and 5-ethyl-2,3-dihydro-2-benzofuranylmethyl)aminoguanidine. The foregoing aminoguanidines areisolated in their free base form or in the form of their acid-additionsalts, preferably sulfates or hydrochlorides. r

The anti-hypertensive activity of the (2,3-dihydro-2-benzofuranylmethyl)guanidines and (2,3-dihydro-2benzofuranylmethyl)aminoguanidines of the invention was determined inunanesthetized renal hypertensive rats using the photoelectrictensometer foot method described by Kersten, et al., J. Lab. Clin. Med.32, 1090 (1947). The method of testing for antihypertensive activity isdescribed briefly as follows: Each compound was administered orally,preferably in the form of its pharmaceutically-acceptable acid-additionsalt, e.g., sulfate or hydrohalide salt, as a suspension in distilledwater with the aid of 1 percent gum tragacanth by stomach tube to groupsof three renalhypertensive rats at each of two to four different doselevels graduated at 0.3 to 0.9 logarithmic intervals. The systolic bloodpressure was determined for each of the three rats per dose level beforemedication and at intervals of l, 2, 4, 6, 24, and 48 hours aftermedication. For control readings, the rats were considered hypertensiveif the systolic blood pressure was 160 mm. Hg or greater. Thepost-medication mean systolic blood pressure for the three rats per doselevel was considered to be lowered significantly if the fall was greaterthan two standard errors from the control mean systolic blood pressure.When tested by the above-described standard procedure, said compounds ofthe invention were found to have anti-hypertensive activitywhenadministered at oral dose levels between about 25 and mg/kg. I

The compounds of the invention can be prepared for use by dissolvingunder sterile conditions a salt form of the compounds in water (or anequivalent amount of-a non toxic acid if the free base is used), or in aphysiologically compatible aqueous medium such as saline, and stored inampules for intramuscular injection. Alternatively, they can beincorporated in unit dosage form as tablets or capsules for oraladministration either alone or in combination with suitable adjuvantssuch as calcium carbonate, starch, lactose, talc, magnesium stearate,gum acacia, and the like. Also, the compounds can be formulated for oraladministration in aqueous alcohol, glycol or oil solutions or oil-wateremulsions in the same manner as conventional medicinal substances areprepared. When used as hypotensive agents, they are formulated and usedin the same manner as conventional hypotensive agents, such as reserpinepreparations, and indeed can be used advantageously in combination withsuch hypotensive agents.

(5-chloro-2,3-dihydro-2-benzofuranylmethyDaminoguanidine was found tohave anti-inflammatory activity as measured by inhibition of car-vrageenin-induced local foot edema in fasted rats generally according tothe standard procedure of C. A. Winter, et al., Proc. Soc. Exptl. & Med.111, 544-547 (1962), as follows: Food is withdrawn from male albinorats, weighing approximately -124 gms., 18 hours prior to a single oralmedication of the test compound.

The compound is administered to at least five rats. One hour followingthe medication, 0.05 ml. of 1 percentaqueous suspension of carrageeninis injected into the plantar tissue of the right hind foot. Three hoursafter injections, the rats are sacrificed and the hind feet cut off atthe tibio-calcaneo-talar joint for subsequent weighing. The observeddifferences between the average edema weight of the control andmedicated rats .is expressed as per cent inhibition of edema. Whentested by the above-described procedure, (5-ch1oro-2,3-dihydro-Z-benzofuranylmethyl)aminoguanidine, when administeredorally in the form of its sesquihydrochloride at 100 mgJkg. was found toproduce '48 percent inhibition of local edema due to carrageenininducedinflammation.

I claim:

1. A compound of the formul NH CHgNHNHa where R is hydrogen or methyl.

CHzNHz a ny sa ant- 14 5. A method according to claim 4 where theguanyletting agent is 2-(lower-alkyl)-2-thiopseudourea.

6. A Z-guanidinylmethyl 2,3-dihydrobenzofuran having the formula 5 R inwhich R is salts thereof.

7. The compound claimed in claim 6; in which R is a hydrogen atom.

hydrogen or methyl, and acid addition

2. (2,3-dihydro-5,7-dimethyl-2-benzofuranylmethyl)-guanidine accordingto claim 1 having formula I where R is methyl. 3.(2,3-dihydro-7-methyl-2-benzofuranylmethyl)guanidine according to claim1 having formula I where R is hydrogen.
 4. A method for preparing acompound according to claim 1 which comprises reacting a compound of theformula
 5. A method according to claim 4 where the guanylating agent is2-(lower-alkyl)-2-thiopseudourea.
 6. A 2-guanidinylmethyl2,3-dihydrobenzofuran having the formula
 7. The compound claimed inclaim 6, in which R is a hydrogen atom.